Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants

Fiona Allum; Xiaojian Shao; Frédéric Guénard; Marie Michelle Simon; Stephan Busche; Maxime Caron; John Lambourne; Julie Lessard; Karolina Tandre; Åsa K. Hedman; Tony Kwan; Bing Ge; Lars Rönnblom; Mark I. McCarthy; Panos Deloukas; Todd Richmond; Daniel Burgess; Timothy D. Spector; André Tchernof; Simon Marceau; Mark Lathrop; Marie Claude Vohl; Tomi Pastinen; Elin Grundberg; Kourosh R. Ahmadi; Chrysanthi Ainali; Amy Barrett; Veronique Bataille; Jordana T. Bell; Alfonso Buil; Emmanouil T. Dermitzakis; Antigone S. Dimas; Richard Durbin; Daniel Glass; Neelam Hassanali; Catherine Ingle; David Knowles; Maria Krestyaninova; Cecilia M. Lindgren; Christopher E. Lowe; Eshwar Meduri; Paola Di Meglio; Josine L. Min; Stephen B. Montgomery; Frank O. Nestle; Alexandra C. Nica; James Nisbet; Stephen O'Rahilly; Leopold Parts; Simon Potter; Johanna Sandling; Magdalena Sekowska; So Youn Shin; Kerrin S. Small; Nicole Soranzo; Gabriela Surdulescu; Mary E. Travers; Loukia Tsaprouni; Sophia Tsoka; Alicja Wilk; Tsun Po Yang; Krina T. Zondervan

doi:10.1038/ncomms8211

Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants

Fiona Allum, Xiaojian Shao, Frédéric Guénard, Marie Michelle Simon, Stephan Busche, Maxime Caron, John Lambourne, Julie Lessard, Karolina Tandre, Åsa K. Hedman, Tony Kwan, Bing Ge, Lars Rönnblom, Mark I. McCarthy, Panos Deloukas, Todd Richmond, Daniel Burgess, Timothy D. Spector, André Tchernof, Simon MarceauMark Lathrop, Marie Claude Vohl, Tomi Pastinen, Elin Grundberg^*, Kourosh R. Ahmadi, Chrysanthi Ainali, Amy Barrett, Veronique Bataille, Jordana T. Bell, Alfonso Buil, Emmanouil T. Dermitzakis, Antigone S. Dimas, Richard Durbin, Daniel Glass, Neelam Hassanali, Catherine Ingle, David Knowles, Maria Krestyaninova, Cecilia M. Lindgren, Christopher E. Lowe, Eshwar Meduri, Paola Di Meglio, Josine L. Min, Stephen B. Montgomery, Frank O. Nestle, Alexandra C. Nica, James Nisbet, Stephen O'Rahilly, Leopold Parts, Simon Potter, Johanna Sandling, Magdalena Sekowska, So Youn Shin, Kerrin S. Small, Nicole Soranzo, Gabriela Surdulescu, Mary E. Travers, Loukia Tsaprouni, Sophia Tsoka, Alicja Wilk, Tsun Po Yang, Krina T. Zondervan

^*Corresponding author for this work

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Abstract

Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

Original language	English
Article number	7211
Number of pages	11
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8211
Publication status	Published - 29 May 2015

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Characterization of functional_ALLUM_Accepted 17Apr2015_GOLD VoRFinal published version, 548 KBLicence: CC BY

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Allum, F., Shao, X., Guénard, F., Simon, M. M., Busche, S., Caron, M., Lambourne, J., Lessard, J., Tandre, K., Hedman, Å. K., Kwan, T., Ge, B., Rönnblom, L., McCarthy, M. I., Deloukas, P., Richmond, T., Burgess, D., Spector, T. D., Tchernof, A., ... Zondervan, K. T. (2015). Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants. Nature Communications, 6, Article 7211. https://doi.org/10.1038/ncomms8211

@article{2257da3278374dec97eb1af3a9142560,

title = "Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants",

abstract = "Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.",

author = "Fiona Allum and Xiaojian Shao and Fr{\'e}d{\'e}ric Gu{\'e}nard and Simon, {Marie Michelle} and Stephan Busche and Maxime Caron and John Lambourne and Julie Lessard and Karolina Tandre and Hedman, {{\AA}sa K.} and Tony Kwan and Bing Ge and Lars R{\"o}nnblom and McCarthy, {Mark I.} and Panos Deloukas and Todd Richmond and Daniel Burgess and Spector, {Timothy D.} and Andr{\'e} Tchernof and Simon Marceau and Mark Lathrop and Vohl, {Marie Claude} and Tomi Pastinen and Elin Grundberg and Ahmadi, {Kourosh R.} and Chrysanthi Ainali and Amy Barrett and Veronique Bataille and Bell, {Jordana T.} and Alfonso Buil and Dermitzakis, {Emmanouil T.} and Dimas, {Antigone S.} and Richard Durbin and Daniel Glass and Neelam Hassanali and Catherine Ingle and David Knowles and Maria Krestyaninova and Lindgren, {Cecilia M.} and Lowe, {Christopher E.} and Eshwar Meduri and {Di Meglio}, Paola and Min, {Josine L.} and Montgomery, {Stephen B.} and Nestle, {Frank O.} and Nica, {Alexandra C.} and James Nisbet and Stephen O'Rahilly and Leopold Parts and Simon Potter and Johanna Sandling and Magdalena Sekowska and Shin, {So Youn} and Small, {Kerrin S.} and Nicole Soranzo and Gabriela Surdulescu and Travers, {Mary E.} and Loukia Tsaprouni and Sophia Tsoka and Alicja Wilk and Yang, {Tsun Po} and Zondervan, {Krina T.}",

year = "2015",

month = may,

day = "29",

doi = "10.1038/ncomms8211",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Allum, F, Shao, X, Guénard, F, Simon, MM, Busche, S, Caron, M, Lambourne, J, Lessard, J, Tandre, K, Hedman, ÅK, Kwan, T, Ge, B, Rönnblom, L, McCarthy, MI, Deloukas, P, Richmond, T, Burgess, D, Spector, TD, Tchernof, A, Marceau, S, Lathrop, M, Vohl, MC, Pastinen, T, Grundberg, E, Ahmadi, KR, Ainali, C, Barrett, A, Bataille, V, Bell, JT, Buil, A, Dermitzakis, ET, Dimas, AS, Durbin, R, Glass, D, Hassanali, N, Ingle, C, Knowles, D, Krestyaninova, M, Lindgren, CM, Lowe, CE, Meduri, E, Di Meglio, P, Min, JL, Montgomery, SB, Nestle, FO, Nica, AC, Nisbet, J, O'Rahilly, S, Parts, L, Potter, S, Sandling, J, Sekowska, M, Shin, SY, Small, KS, Soranzo, N, Surdulescu, G, Travers, ME, Tsaprouni, L, Tsoka, S, Wilk, A, Yang, TP & Zondervan, KT 2015, 'Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants', Nature Communications, vol. 6, 7211. https://doi.org/10.1038/ncomms8211

TY - JOUR

T1 - Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants

AU - Allum, Fiona

AU - Shao, Xiaojian

AU - Guénard, Frédéric

AU - Simon, Marie Michelle

AU - Busche, Stephan

AU - Caron, Maxime

AU - Lambourne, John

AU - Lessard, Julie

AU - Tandre, Karolina

AU - Hedman, Åsa K.

AU - Kwan, Tony

AU - Ge, Bing

AU - Rönnblom, Lars

AU - McCarthy, Mark I.

AU - Deloukas, Panos

AU - Richmond, Todd

AU - Burgess, Daniel

AU - Spector, Timothy D.

AU - Tchernof, André

AU - Marceau, Simon

AU - Lathrop, Mark

AU - Vohl, Marie Claude

AU - Pastinen, Tomi

AU - Grundberg, Elin

AU - Ahmadi, Kourosh R.

AU - Ainali, Chrysanthi

AU - Barrett, Amy

AU - Bataille, Veronique

AU - Bell, Jordana T.

AU - Buil, Alfonso

AU - Dermitzakis, Emmanouil T.

AU - Dimas, Antigone S.

AU - Durbin, Richard

AU - Glass, Daniel

AU - Hassanali, Neelam

AU - Ingle, Catherine

AU - Knowles, David

AU - Krestyaninova, Maria

AU - Lindgren, Cecilia M.

AU - Lowe, Christopher E.

AU - Meduri, Eshwar

AU - Di Meglio, Paola

AU - Min, Josine L.

AU - Montgomery, Stephen B.

AU - Nestle, Frank O.

AU - Nica, Alexandra C.

AU - Nisbet, James

AU - O'Rahilly, Stephen

AU - Parts, Leopold

AU - Potter, Simon

AU - Sandling, Johanna

AU - Sekowska, Magdalena

AU - Shin, So Youn

AU - Small, Kerrin S.

AU - Soranzo, Nicole

AU - Surdulescu, Gabriela

AU - Travers, Mary E.

AU - Tsaprouni, Loukia

AU - Tsoka, Sophia

AU - Wilk, Alicja

AU - Yang, Tsun Po

AU - Zondervan, Krina T.

PY - 2015/5/29

Y1 - 2015/5/29

N2 - Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

AB - Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

UR - http://www.scopus.com/inward/record.url?scp=84931274676&partnerID=8YFLogxK

U2 - 10.1038/ncomms8211

DO - 10.1038/ncomms8211

M3 - Article

AN - SCOPUS:84931274676

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7211

ER -

Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants

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